Carolina Breast Cancer Study:
Breast cancer subtypes and race
Robert Millikan
University of North Carolina
Chapel Hill, NC
Research Questions
Could breast cancer represent more
than one disease?
Can different subtypes of breast
cancer help to explain racial
disparities?
Research Question #1
A major problem in breast cancer research is
tumor heterogeneity:
Patients do not respond uniformly to treatment.
Could breast cancer represent more than one
disease?
Clinical and Pathologic Staging of
Breast Cancer
Traditional Staging
Breast cancer patients receive a clinical
stage at initial diagnosis.
The definitive stage is based upon
pathologic information obtained at the
time of surgical removal of the primary
tumor and regional lymph nodes.
TNM system.
New Paradigm
“Biology trumps staging.” ASCO 2008
Differences in underlying biology of
breast tumors determine clinical
course and response to therapy.
How do we get at the underlying
biology of breast cancer?
How do we apply this knowledge to:
• Prognosis
• Predicting therapeutic response
• Understanding disease causation
• Prevention
Biology
IHC / TMAs
mRNA profiling
Histology
TNM
Staging
Biology
IHC / TMAs
mRNA profiling
Histology
TNM
Staging
TNM staging
• T stands for tumor (its size and how far it
has spread within the breast and to nearby
organs).
• N stands for spread to lymph nodes (the
number of nodes where cancer is
detected).
• M is for metastasis (spread to distant
organs).
TNM staging
• TNM staging helps understand
survival (prognosis).
• It does not tell us how to treat, what
drugs to give (predict therapeutic
response).
New paradigm:
Use gene expression profiling
and immunohistochemistry to
understand the underlying biology
Biology
IHC / TMAs
mRNA profiling
Histology
TNM
Staging
Identification of Breast
Cancer Subtypes
DNA microarray-based gene expression profiling.
Perou and colleagues (UNC Chapel Hill)
8,102 genes →1,753 genes→ 496 genes “intrinsic”
Nature 406: 747-52 (2000).
“Intrinsic” breast cancer
subtypes
Basal-like
ER- PR- HER2- ck5/6+ and /or HER1+
Luminal A
ER+ and/or PR+ HER2-
Luminal B
ER+ and/or PR+ HER2+
HER2+ / ER –
ER- PR- HER2+
“Unclassified”
Negative for all five markers
Biology
IHC / TMAs
mRNA profiling
Histology
Clinical
Staging
Algorithm for breast cancer subtypes
All cases
ER - PR -
HER2 -
EGFR
- CK5/6 –
Unclassified
ER+ or PR +
HER2 +
HER2 +
HER2+/ER-
Luminal B
HER2 -
EGFR + or CK5/6 +
Basal-like
Luminal A
Carolina Breast Cancer Study
Carolina Breast Cancer Study
The Carolina Breast Cancer Study (CBCS) is
an ongoing population-based epidemiologic
study examining the causes of breast cancer in
African American and white women.
The study began in 1993 and continued
enrolling participants until 2001
(Phase 1 and 2).
We are opening the study again from 2008 to
2012 (Phase 3).
Distribution of IHC subtypes in
invasive breast cancer
(Phase 1 CBCS)
Luminal A
(ER+ PR+ HER2-)
51%
Luminal B
(ER+ PR+ HER2+)
16%
Basal-like
(ER- PR- HER2- ck5/6+ and/or HER1+)
20%
HER2+, ER(HER2+,ER-, PR-)
7%
Unclassified
(negative for all five IHC markers)
6%
Basal-like subtype
Increased proliferation (P < 0.0001)
Higher grade (P < 0.0001)
Poor differentiation (P < 0.003)
P53 mutation positive (P< 0.001)
JAMA 2006, 295: 2492-2502.
Breast Cancer Specific Survival
Mean survival
(years)
Luminal A
Luminal B
Basal-like
HER2+/ER-
7.6
7.7
4.9
6.7
Log-rank test P < 0.0001
Percent
survival
84%
87%
75%
52%
Luminal A
Luminal B
Unclassified
Basal-like
HER2+/ERP <0.0001
Breast Cancer Specific Survival Time in Years
Note: Prior to introduction of herceptin.
Basal-like subtype of breast
cancer
No proven therapeutic targets
ER negative, PR negative:
Can’t use Tamoxifen or anti-estrogens
HER2 negative:
Can’t use Herceptin
Tailored Therapy
ER positive
Luminal A
ER negative
Luminal B
HORMONAL
THERAPY
BASAL-LIKE
HER2
HERCEPTIN
EGFR
BASAL
THERAPEUTIC
TARGETS?
Gefitinib, erlotinib
Lapatinib
CI-1033
BRCA1 defective
DNA damage
PARP inhibitors
C-kit
Imatinib/Gleevec
Research Question #2:
Why is breast cancer mortality higher
among African American women
compared with white women?
Younger white women
6.3 deaths / 100,000 per year
Younger African American women
11.0 deaths / 100,000 per year
Basal-like breast cancer is more
common in younger African
American women.
Our observation may help to explain why
breast cancer mortality is higher among
younger African American women.
Distribution of subtypes according to race
and menopausal status (CBCS Phase 1)
Premenopausal
African American
Postmenopausal
African American
Premenopausal
Whites
Postmenopausal
Whites
Luminal A
36%
59%
51%
58%
Luminal B
9%
16%
18%
16%
Basal-like
39%
14%
16%
16%
HER2+ / ER-
9%
7%
6%
6%
Unclassified
6%
4%
10%
4%
Chi square P =
0.0001
Basal-like breast cancer in North Carolina
(Carolina Breast Cancer Study)
45
40
35
30
25
20
15
10
5
0
AA < 50
AA >= 50
W < 50
W >= 50
Latest CBCS results
Younger African American women have a higher
risk of basal-like breast cancer because they
have a higher prevalence of risk factors for the
disease:
Higher waist hip ratio
Higher parity
Lower breastfeeding
Several of these risk factors are modifiable.
Breast Cancer Res Trt 2008, 109: 123-139
Public Health Significance
These results stand in stark contrast to
recent news commentaries (NY Times, AP,
Science) suggesting that basal-like breast
cancer represents:
The “exclusive property” of a specific age
and racial group.
A disease caused solely by “genetic
inheritance.”
Summary
• Breast cancer appears to be more than
one disease
• Younger African American women have a
higher frequency of basal-like breast
cancer, which could contribute to higher
breast cancer mortality
• Basal-like breast cancer may be
preventable